The Relationship between Electrocardiographic Changes and Prognostic Factors in Severely Symptomatic Pulmonary Hypertension.

Background
The prognostic role of the electrocardiogram (ECG) in PH is not fully known. We aimed to evaluate ECG abnormalities in severe PH, the association of ECG patterns with known prognostic factors and to determine whether ECG abnormalities were associated with decreased survival in patients with severe PH.


Materials and Methods
Fifty-two patients with severe PH were included. Clinical assessment included basic demographics, complete physical examination, determination of WHO FC, measurement of N-terminal pro-BNP, 12-lead electrocardiography, transthoracic echocardiography, right heart catheterization (RHC) and six minute walk test (6MWT).


Results
Heart rate was correlated with NT-proBNP (r=0.54; p-value: 0.0001) and was higher in patients with severe RV dysfunction (93±12 vs. 83±4 bpm in moderate RV dysfunction). P-pulmonale was present in 51.9% of the patients and was significantly associated with severe RV dysfunction. qR in V1 (48.1%) was significantly associated with 6MWT and severe RV dysfunction. Overall, 10 patients died. Based on Kaplan-Meier results, median survival time was 38 months and estimated survival at 1 year, 3 years, and 5 years was 88%, 80% and 71 % respectively. In Cox regression analysis WHO FC, 6MWT, pericardial effusion, NT-pro BNP, heart rate, ST depression in V1 to V3, and presence of qR in V1 were predictors of mortality. After controlling for covariates, only NT-proBNP was independently associated with decreased survival.


Conclusion
ECG changes including P-pulmonale, qR pattern in V1, and heart rate indicative of right ventricular dysfunction are associated with prognostic factors in severe PH and may be a useful tool in the follow-up.


INTRODUCTION
Pulmonary hypertension (PH) is defined as mean pulmonary artery pressure 25 mmHg or more at rest, measured by right heart catheterization (1). PH consists of a group of disorders characterized by progressive thickening of pulmonary vasculature, leading to right ventricular dysfunction and death (2). PH is more common in females (3) and its true prevalence is unclear, probably due to broad range of etiologies. However, the estimated prevalence in adults is 6 to 15 cases per one million in different registries (4,5). Despite recent advances in the treatment of patients with PH, the prognosis in many patients remains poor (6). The estimated mortality rate for PH was 6.5 per 100,000 in the United States in 2010 (7). The type natriuretic peptide (NT-proBNP) and Right Ventricular (RV) dysfunction are known predictors of prognosis in PH (8)(9)(10)(11)(12).
Electrocardiogram is a simple, inexpensive, and noninvasive test. However, its prognostic role in patients with PH remains uncertain. Common ECG patterns seen in PH include right atrial abnormalities, right axis deviation, right ventricular hypertrophy with strain pattern (13). In a study by Bossone et al in 2002, the presence of Ppulmonale and qR in V1 were independent predictors of increased mortality in patients with primary PH (14). In another study, the presence of qR in V1 was shown to be a sign of advanced pulmonary arterial hypertension and was a significant prognostic factor (15). In a recent study, right axis deviation (RAD) of QRS complex was present in 23% of patients with PH and was associated with a high positive predictive value (92-93%) for PH (16). Therefore, in this study we aimed to evaluate the distribution of ECG abnormalities in our severe PH patients and determine the association of ECG patterns with established prognostic factors and mortality in patients with severe PH.   (19).Complete RBBB was defined according to AHA/ACCF/HRS Recommendations: QRS duration ≥120 ms, rsr′, rsR′, or rSR′ in leads V1 or V2 (The R′ or r′ deflection is usually wider than the initial R wave) or a wide and notched R wave in V1 and/or V2. S wave of greater duration than R wave or > 40 ms in leads I and V6

MATERIALS AND METHODS
,Normal R peak time in leads V5 and V6 but >50 ms in lead V1 (19). Incomplete RBBB was defined by QRS duration between 110 and 120 ms. Other criteria are the same as for complete RBBB (19). ECG criteria of RVH was defined as presence of qR in V1, S>R in leads I, II, III (S1S2S3), and S1Q3 pattern (20) .

Statistical analysis
Mann-Whitney U test was used to compare NT-proBNP and 6MWT in the presence of ECG parameters and other qualitative variables. Chi-squared or Fisher exact tests were used for comparing qualitative variables.
Spearman correlation was used for testing correlation between heart rate and NT-proBNP and 6MWT. Survival times are described using Kaplan-Meier survival estimates.
Variables were tested as possible predictors of mortality using Cox proportional hazard model and Hazard ratios (HRs) and 95% confidence intervals (CIs) are reported.
First, each variable was entered in the model, individually.
Then, variables with p-value more than 0.2 entered multivariate analysis. The data were analyzed using SPSS software version 18 (Chicago, IL, USA). All reported pvalues are two-tailed, and p-values of less than 0.05 were considered statistically significant. Clinical characteristic of the study population are showed in Table 1. Presence of qR was also associated with higher NT-proBNP levels (1992±856 versus 1220±863, p-value=0.002) and severe RV dysfunction (p-value=0.004). S1S2S3 and S1Q3 patterns were not significantly associated with prognostic factors .
There were no lost to follow-up cases. Overall ten patients died. The cause of death was progressive right heart failure in all cases. For the remaining 42 patients, survival times were censored at the time of last visit. Median survival time was 38 months (Figure 1). The estimated proportion of patients surviving at 1 year, 3 years, and 5 years were 88% (95%CI, 78 to 98%), and 80% (95% CI, 68% to 92%), and 71% (95% CI, 51% to 91%) respectively.  Table 2).

DISCUSSION
In the present study, P-pulmonale, heart rate, and qR in V1 were associated with severe RV dysfunction; heart rate and qR in V1 were significantly associated with 6MWD; heart rate was correlated with NT-proBNP levels; WHO FC, 6MWD, presence of pericardial effusion on echocardiography, NT-proBNP level, heart rate, ST segment depression in V1-V3, and qR pattern in V1 were significantly associated with mortality; while only NT-proBNP was independent predictor of mortality.   (15) .
RV dysfunction also leads to decreased stroke volume, and increased neuro-hormonal stimulation of the myocardium probably explains increased heart rate in PH patients (14). Bossone et al. showed that increased heart rate increases the risk of death (14). In our study increased heart rate was associated with higher NT-proBNP, poorer performance in 6MWT, severe RV dysfunction and death. However, after adjustment for possible cofounders, heart rate did not remain an independent predictor of mortality.
In our analyses, Class IV WHO FC and lower performance in 6MWT were significantly associated with higher mortality. It was in line with previous studies in which WHO FC and 6MWD were independent predictors of survival (9,23,24). Moreover, our analyses showed higher mortality in patients with pericardial effusion on echocardiography. Previous investigators reported that pericardial effusion on echocardiography reflects the severity of right heart failure and predicts adverse outcomes in patients with primary pulmonary hypertension (25). The US Registry to Evaluate Early and There are several limitations to this study. We did not re-evaluate ECG changes during and at the end of the follow-up period in most of the patients. So, future studies with larger sample size and monitoring of the prognostic markers at intervals can better reveal correlation of ECG parameters with disease severity and progression.

CONCLUSION
Electrocardiographic changes including P-pulmonale, qR pattern in V1, and heart rate were associated with RV dysfunction and prognostic markers in patients with severe pulmonary hypertension.